Alcohol dependence, schizophrenia and anxiety disorders are comorbid disorders that occur at a remarkably high rate but there are presently very few treatments available for people with these comorbid mental diseases. Alcohol withdrawal may be one common factor in the pathogenesis of alcohol dependence and comorbid mental disorders. Alcohol withdrawal can damage the brain and produce cognitive and emotional impairments in alcohol-dependent individuals that are similar to that seen in people with schizophrenia and anxiety disorders. Evidence suggests that activating the 3',5'-cyclic adenosine monophosphate (cAMP) second messenger signaling pathway may reduce the behavioral effects of alcohol withdrawal. The broad, long-term objective of this exploratory R21 project is to explore the therapeutic potential of two promising drugs that raise intracellular cAMP levels, forskolin and rolipram, to reduce physical, cognitive, and emotional signs of alcohol withdrawal in mice. The goal of Specific Aim 1 is to explore the effects of forskolin and rolipram on the physical signs of alcohol withdrawal using handling-induced convulsions to assess withdrawal following chronic alcohol treatment. The goal of Specific Aim 2 is to explore the effects of forskolin and rolipram on cognitive signs of alcohol withdrawal using pre-pulse inhibition of the acoustic startle response to assess withdrawal following chronic alcohol treatment. The goal of Specific Aim 3 is to explore the effects of forskolin and rolipram on emotional signs of alcohol withdrawal (anxiety) using the fear-potentiated startle response to assess withdrawal following chronic alcohol treatment. We will also measure phosphorylated cAMP response element binding protein in three brain regions to provide a biological marker for cAMP activity under the proposed test conditions. The results of this exploratory R21 project may reveal that activation of the adenylate cyclase-cAMP signaling pathway reduces alcohol withdrawal effects and could improve cognitive and emotional function in people with alcohol dependence and comorbid mental diseases. PUBLIC HEALTH RELEVANCE: Alcohol dependence, schizophrenia and anxiety disorders are common comorbid disorders in that they are frequently found to occur together in the same individual. The goal of this project is to develop new models to assess alcohol dependence and comorbid conditions and identify two promising, novel therapeutic drugs to treat these conditions.